Viral infection has been associated with the development of type 1 diabetes (T1D) but a causal role for viruses remains unproven. Studies in animals have been problematic because of differences in host species- specific susceptibility and immune responses to candidate viral pathogens such as coxsackie B virus (CVB). In order to better evaluate the impact of viruses in causing human T1D, we developed a viral infection model in immunodeficient mice bearing human islet grafts that are crucial for glycemic control. In this model, infection with CVB led to diabetes in nearly half of all infected animals. Human islet grafts from CVB4-infected mice contained viral RNA, expressed viral protein, and had reduced insulin compared to grafts from mock-infected mice. Gene expression profiles from the human grafts also revealed induction of signature genes, such as multiple interferon stimulated genes. In this platform CVB4 infects human beta cells that subsequently become severely dysfunctional with diminished insulin production, leading to diabetes. In the proposed study, we will examine: 1) whether the functional destruction of beta cells is due to a deleterious innate response, direct destruction by virus, or a combination of the two, and 2) what are mechanisms of beta cell dysfunction and/or death. Further investigation of viral infection of human islets using combined in vitro and in vivo approaches will lead to a clearer understanding of the innate factors that contribute to virus-induced T1D. These studies will identify and characterize mutant viruses that are not diabetogenic and thus potential vaccine candidates.